Pharmaceutical composition for modified release

ABSTRACT

A pharmaceutical composition for modified release, comprising (1) (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide, or a pharmaceutically acceptable salt thereof, (2) at least one additive which ensures penetration of water into the pharmaceutical composition and which has a solubility such that the volume of water required for dissolving 1 g of the additive is 10 mL or less, and (3) a hydrogel-forming polymer having an average molecular weight of approximately 100,000 or more, or a viscosity of 12 mPa·s or more at a 5% aqueous solution at 25° C. is disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 12/568,313, filed Sep. 28, 2009, which application claims thebenefit of priority to U.S. Patent Application No. 61/101,338, filedSep. 30, 2008, the teachings of which are hereby incorporated byreference.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition formodified release capable of reducing food effects, which are observed inconventional tablets, by combining an active ingredient with specificingredients to control a releasing rate of the active ingredient.

More particularly, the present invention relates to a pharmaceuticalcomposition comprising(R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]aceticacid anilide or a pharmaceutically acceptable salt thereof, an additivewhich ensures penetration of water into the pharmaceutical composition(hereinafter sometimes referred to as a hydrophilic base), and a polymerwhich forms a hydrogel, in which the changes in AUC and Cmax caused bythe intake of food can be decreased by controlling a releasing rate ofthe active ingredient.

BACKGROUND ART

(R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]aceticacid anilide has been created by Astellas Pharma Inc., and it has beenreported that this compound has not only both an activity of promotinginsulin secretion and an activity of enhancing insulin sensitivity, butalso an antiobestic activity and an antihyperlipemic activity based onan activity of selectively stimulating a β3 receptor, and is useful intreating diabetes (see, for example, patent literature 1).

Further, it has been reported that the compound can be used as atherapeutic agent for overactive bladder, such as overactive bladderaccompanied by prostatic hyperplasia, or overactive bladder accompaniedby urinary urgency, urinary incontinence, and urinary frequency (see,for example, patent literature 2).

A clinical trial of(R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]aceticacid anilide in the form of conventional formulations revealeddisadvantages, for example, that pharmacokinetic data unexpectedlyvaried according to the presence or absence of the intake of food (notpublished). For example, the rate of decrease of Cmax in a fed state was67%, and the rate of decrease of AUC in the fed state was 47%, incomparison with those in a fasted state. In this case, Cmax in thefasted state was three times higher than that in the fed state. Theseproblems are considered to be raised by, for example, the changes inpharmacokinetics caused by food, and therefore, the development of aformulation capable of avoiding the effects by food intake is desired.

As a technique of preparing a formulation for modified release, ahydrogel sustained release tablet containing an additive which ensurespenetration of water into the tablet, and a hydrogel-forming polymer isdisclosed (see, for example, patent literature 3).

However, patent literature 3 does not refer to(R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]aceticacid anilide, and further improvements are needed to produce apharmaceutical composition.

CITATION LIST Patent Literature

-   [patent literature 1] International Publication No. WO 99/20607    (Example 41)-   [patent literature 2] International Publication No. WO 2004/041276-   [patent literature 3] International Publication No. WO 94/06414

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a pharmaceuticalcomposition for modified release comprising(R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]aceticacid anilide or a pharmaceutically acceptable salt thereof, in which thepharmaceutical composition has efficacy the same as or higher than thoseof conventional formulations and has no limitations on food intake, anda process of manufacturing the pharmaceutical composition.

Solution to Problem

The elimination half-life (T_(1/2)) of(R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]aceticacid anilide is long (approximately 18 to 24 hours), and thus, aformulation thereof for modified release is not necessarily needed tomaintain its blood level. Taking into consideration the results of theclinical trial described above, the present inventors conductedintensive studies to design the formulation by paying attention to thecontrol of a release rate of the drug from a formulation to the extentthat the release is not affected by food intake or the like, rather thanthe addition of release control.

On the basis of blood concentration profiles (in a fasted state/afterthe intake of food) after administration of a conventional formulation(rapid release formulation), the absorption rate of the drug in a fedstate was calculated by a deconvolution method to predict continuousabsorption for about 4 hours. The present inventors considered from thisresult that a formulation capable of continuous drug release for 4 hoursor more would be able to reduce the effects by food, because the drugrelease from the formulation would become the rate-limiting step forabsorption.

The present inventors carried out a clinical trial in human using threetypes of formulations in which the release rate of the drug wascontrolled (Time when the release percentage of the drug from the unitformulation was 80% (T80%)=4 hr, 6 hr, and 10 hr), and found that allformulations could reduce the effects by food, to complete the presentinvention.

It is generally known that the retention time in the stomach and therelease rate of formulations for modified release vary according to thepresence or absence of food intake, and as a result, there is apossibility that blood concentration profiles is changed. However,surprisingly, when using this formulation, the change of the bloodconcentration profiles was small in the presence or absence of foodintake.

The present invention is characterized by providing a pharmaceuticalcomposition for modified release which is not affected by the effects offood intake and exhibits a decreased change in AUC or Cmax.

The present invention provides:

-   [1] a pharmaceutical composition for modified release,    comprising (1)    (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic    acid anilide, or a pharmaceutically acceptable salt thereof, (2) at    least one additive which ensures penetration of water into the    pharmaceutical composition and which has a solubility such that the    volume of water required for dissolving 1 g of the additive is 10 mL    or less, and (3) a hydrogel-forming polymer having an average    molecular weight of approximately 100,000 or more, or a viscosity of    12 mPa·s or more at a 5% aqueous solution at 25° C.;-   [2] the pharmaceutical composition for modified release of [1],    wherein the additive which ensures penetration of water into the    pharmaceutical composition is one compound, or two or more compounds    selected from the group consisting of polyethylene glycol,    polyvinylpyrrolidone, D-mannitol, D-sorbitol, xylitol, lactose,    sucrose, anhydrous maltose, D-fructose, dextran, glucose,    polyoxyethylene hydrogenated castor oil, polyoxyethylene    polyoxypropylene glycol, polyoxyethylene sorbitan higher fatty acid    ester, sodium chloride, magnesium chloride, citric acid, tartaric    acid, glycine, β-alanine, lysine hydrochloride, and meglumine;-   [3] the pharmaceutical composition for modified release of [2],    wherein the additive which ensures penetration of water into the    pharmaceutical composition is one compound, or two or more compounds    selected from the group consisting of polyethylene glycol,    polyvinylpyrrolidone, D-mannitol, lactose, sucrose, sodium chloride,    and polyoxyethylene polyoxypropylene glycol;-   [4] the pharmaceutical composition for modified release of any one    of [1] to [3], wherein an amount of the additive which ensures    penetration of water into the pharmaceutical composition is 5% by    weight to 75% by weight with respect to the total weight of the    pharmaceutical composition;-   [5] the pharmaceutical composition for modified release of [4],    wherein an amount of the additive which ensures penetration of water    into the pharmaceutical composition is 5% by weight to 70% by weight    with respect to the total weight of the pharmaceutical composition;-   [6] the pharmaceutical composition for modified release of any one    of [1] to [5], wherein the hydrogel-forming polymer is one compound,    or two or more compounds selected from the group consisting of    polyethylene oxide, hydoxypropyl methylcellulose, hydroxypropyl    cellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose,    and a carboxyvinyl polymer;-   [7] the pharmaceutical composition for modified release of [6],    wherein the hydrogel-forming polymer is one compound, or two or more    compounds selected from the group consisting of polyethylene oxide,    hydoxypropyl methylcellulose, and hydroxypropyl cellulose;-   [8] the pharmaceutical composition for modified release of any one    of [1] to [7], wherein an amount of the hydrogel-forming polymer is    1% by weight to 70% by weight with respect to the total weight of    the pharmaceutical composition;-   [9] the pharmaceutical composition for modified release of any one    of [1] to [8], further comprising an antioxidant;-   [10] the pharmaceutical composition for modified release of [9],    wherein the antioxidant is one compound, or two or more compounds    selected from the group consisting of butyl hydroxytoluene, propyl    gallate, and sodium ascorbate;-   [11] the pharmaceutical composition for modified release of claim    10, wherein the antioxidant is butyl hydroxytoluene;-   [12] the pharmaceutical composition for modified release of any one    of [9] to [11], wherein an amount of the antioxidant is 0.025% by    weight to 0.25% by weight;-   [13] the pharmaceutical composition for modified release of any one    of [1] to [12], further comprising a stabilizer;-   [14] the pharmaceutical composition for modified release of [13],    wherein the stabilizer is one compound, or two or more compounds    selected from the group consisting of yellow ferric oxide, red    ferric oxide, and black iron oxide;-   [15] the pharmaceutical composition for modified release of [14],    wherein the stabilizer is yellow ferric oxide and/or red ferric    oxide;-   [16] the pharmaceutical composition for modified release of any one    of [13] to [15], wherein an amount of the stabilizer is 0.05% by    weight to 1% by weight;-   [17] a process of manufacturing a pharmaceutical composition for    modified release, characterized by comprising mixing (1)    (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic    acid anilide, or a pharmaceutically acceptable salt thereof with (2)    at least one additive which ensures penetration of water into the    pharmaceutical composition and which has a solubility such that the    volume of water required for dissolving 1 g of the additive is 10 mL    or less and (3) a hydrogel-forming polymer having an average    molecular weight of approximately 100,000 or more, or a viscosity of    12 mPa·s or more at a 5% aqueous solution at 25° C., wherein an    amount of the additive is 5% by weight to 75% by weight with respect    to the total weight of the pharmaceutical composition, and an amount    of the hydrogel-forming polymer is 1% by weight to 70% by weight    with respect to the total weight of the pharmaceutical composition;-   [18] the process of [17], wherein the additive which ensures    penetration of water into the pharmaceutical composition is one    compound, or two or more compounds selected from the group    consisting of polyethylene glycol, polyvinylpyrrolidone, D-mannitol,    D-sorbitol, xylitol, lactose, sucrose, anhydrous maltose,    D-fructose, dextran, glucose, polyoxyethylene hydrogenated castor    oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene    sorbitan higher fatty acid ester, sodium chloride, magnesium    chloride, citric acid, tartaric acid, glycine, β-alanine, lysine    hydrochloride, and meglumine; and-   [19] the process of [17] or [18], wherein the hydrogel-forming    polymer is one compound, or two or more compounds selected from the    group consisting of polyethylene oxide, hydoxypropyl    methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose    sodium, hydroxyethyl cellulose, and a carboxyvinyl polymer.

As formulation techniques for reducing or avoiding the changes inpharmacokinetics such as AUC or Cmax accompanied by food intake, aformulation technique concerning a sustained-release pharmaceuticalcomposition containing tamsulosin hydrochloride is disclosed (seeJapanese Unexamined Patent Publication (Kokai) No. 2005-162736 andJapanese Unexamined Patent Publication (Kokai) No. 2005-162737). Thisformulation technique is limited to tamsulosin, and applied to aformulation containing the drug at a low dose (0.4 mg per unitformulation). This formulation enables to control the release oftamsulosin therefrom by being mainly composed of a sustained-releasebase. By contrast, the pharmaceutical composition contains the drug at ahigh dose (i.e., high content per unit formulation), and it isconsidered difficult to control the release rate of the drug from aformulation containing the sustained-release base at a low content, andtherefore, the present invention is technically quite different from theformulation disclosed in these references.

Effects of Invention

According to the present invention, a pharmaceutical composition formodified release which has no limitations on food intake and is stable(for example, reduction of changes in a sequential dissolution profile)can be provided.

Further, a pharmaceutical composition for modified release in which AUCis not reduced can be provided.

With respect to a conventional formulation, the rate of decrease of Cmaxin the fed state was 67% in comparison with that in a fasted state. Bycontrast, with respect to the pharmaceutical composition for modifiedrelease of the present invention, the rate of decrease of Cmax in thefed state was 42% in comparison with that in a fasted state, and thisresult showed that reduction of Cmax caused by food intake could besignificantly alleviated by forming its formulation into thepharmaceutical formulation for modified release.

BRIEF DESCRIPTION OF DRAWINGS

The FIGURE is a graph showing dissolution profiles of the pharmaceuticalcomposition for modified release prepared in Example 11, and the timecourses thereof.

DESCRIPTION OF EMBODIMENTS

The pharmaceutical composition for modified release of the presentinvention will be explained hereinafter.

The term “rapid release formulation (conventional formulation)” as usedherein means a formulation in which the dissolution rate of the drugfrom the formulation is 85% or more after 30 minutes from the beginninga dissolution test, which is carried out in accordance with adissolution test (paddle method) described in the United StatesPharmacopoeia under the conditions that 900 mL of an appropriate testfluid (such as a USP buffer, pH 6.8) is used and the paddle rotationspeed is 100 rpm. Alternatively, the term means a formulation in whichthe dissolution rate of the drug from the formulation is 85% or moreafter 30 minutes from the beginning a dissolution test, which is carriedout in accordance with a dissolution test, method 2 described in theJapanese Pharmacopoeia under the conditions that 900 mL of anappropriate test fluid (such as a Mc. Ilvain buffer, pH 6.8) is used andthe paddle rotation speed is 50 rpm.

The term “pharmaceutical composition for modified release” as usedherein means a formulation in which the dissolution rate of the drugfrom the formulation is less than 85% after 30 minutes from thebeginning a dissolution test carried out under the above conditions, andthe drug release is controlled to the extent that the effects by foodare reduced. More particularly, it is a formulation in which an additive(hydrophilic base) which ensures penetration of water into theformulation is combined with a polymer which forms a hydrogel.

The wording “the effects by food are reduced” as used herein means, forexample, a 10% reduction, a 20% reduction in another embodiment, and a30% reduction in still another embodiment, in comparison with Cmax of aconventional formulation. Alternatively, the term means, for example, a10% reduction with respect to the rates of decrease of Cmax and AUC inadministration after food intake, in comparison with Cmax and AUC inadministration in the fasted state, a 20% reduction in anotherembodiment, and a 30% reduction in still another embodiment.

The rates of decrease of Cmax and AUC are calculated by the followingequations:

Rd(Cmax)=[Cmax(FS)−Cmax(FI)]×100/Cmax(FS)

Rd(AUC)=[AUC(FS)−AUC(FI)]1×100/AUC(FS)

-   Rd(Cmax): Rate of decrease of Cmax (%)-   Cmax(FS): Cmax in administration in the fasted state-   Cmax(FI): Cmax in administration after food intake-   Rd(AUC): Rate of decrease of AUC (%)-   AUC(FS): AUC in administration in the fasted state-   AUC(FI): AUC in administration after food intake

The term “formulation in which the effects by food are reduced” as usedherein means a formulation in which the dissolution rate of the drugfrom the formulation is 75% or less after 1.5 hours and 100% or lessafter 4 hours from the beginning a dissolution test, which is carriedout under the above conditions [in accordance with a dissolution test(paddle method) described in the United States Pharmacopoeia under theconditions that 900 mL of an appropriate test fluid (such as a USPbuffer, pH 6.8) is used and the paddle rotation speed is 50 to 200 rpm].In another embodiment, the term means a formulation in which thedissolution rate of the drug from the formulation is 75% or less after1.5 hours and 75% or more to 100% or less after 7 hours.

The term “stable” as used herein means that it is stable against, forexample, heat, temperature, humidity, or light. More particularly, theterm means that, for example, when a plastic bottle is filled with apharmaceutical composition and sealed, and then, the bottle is preservedfor three months under the conditions at 40° C. and 75% RH or at 60° C.,the change in the dissolution rate at the point showing a dissolutionrate of 50% is within ±5% or less. Alternatively, the term means that,for example, when a pharmaceutical composition is exposed to 1.2 millionLux·hr of light, the change in the dissolution rate at the point showinga dissolution rate of 50% is within +5% or less.

(R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]aceticacid anilide (hereinafter sometimes referred to as compound A) isrepresented by the following structural formula.

Compound A may be used in a free form which is not a salt, and may forma salt with an acid in other embodiments. Examples of such a saltinclude an acid addition salt with a mineral acid such as hydrochloricacid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid,phosphoric acid, or the like; and an acid addition salt with an organicacid such as formic acid, acetic acid, propionic acid, oxalic acid,malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid,malic acid, citric acid, tartaric acid, carbonic acid, picric acid,methanesulfonic acid, ethanesulfonic acid, glutamic acid, or the like.

The dose of compound A may be appropriately selected in accordance withsymptom, age, sex, and the like of the patient to be treated. The dailydose of compound A for oral administration to an adult is generally 0.01to 100 mg/kg, which is administered once or divided into two to fourdoses per day.

The content of compound A per formulation is, for example, 1% by weightto 70% by weight, 5% by weight to 70% by weight in another embodiment,and 5% by weight to 50% by weight in still another embodiment. Thecontent of compound A per formulation is 1 mg to 500 mg, and 10 mg to200 mg in another embodiment.

It is necessary that the hydrogel-forming polymer used in the presentinvention can control the release rate of the drug, to the extent thatthe blood concentration profile of the drug is not affected by thepresence or absence of food intake.

The molecular weight of the hydrogel-forming polymer is, for example,100,000 or more, 100,000 to 8,000,000 in another embodiment, 100,000 to5,000,000 in still another embodiment, and 100,000 to 2,000,000 in stillanother embodiment. The viscosity of the hydrogel-forming polymer is,for example, 12 mPa·s or more in a 5% aqueous solution at 25° C.; 12mPa·s or more in a 5% aqueous solution at 25° C., and 40,000 mPa·s orless in a 1% aqueous solution at 25° C. in another embodiment; 400 mPa·sor more in a 2% aqueous solution at 25° C., and 7,500 mPa·s or less in a1% aqueous solution at 25° C. in still another embodiment; and 400 mPa·sor more in a 2% aqueous solution at 25° C., and 5,500 mPa·s or less in a1% aqueous solution at 25° C. in still another embodiment.

In the pharmaceutical composition for modified release of the presentinvention, the release period of time of the drug from the formulationcan be arbitrarily controlled by adjusting the viscosity of the polymerwhich is used as the hydrogel-forming polymer.

The hydrogel-forming polymer used in the present invention is notparticularly limited, so long as the release of the drug can becontrolled to the extend that the effects of food on compound A may bereduced. Examples of the hydrogel-forming polymer include polyethyleneoxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose,carboxymethyl cellulose sodium, hydroxyethyl cellulose, and carboxyvinylpolymers. Examples of the hydrogel-forming polymer in another embodimentinclude polyethylene oxide, hydroxypropyl methylcellulose, andhydroxypropyl cellulose.

Examples of polyethylene oxide (hereinafter sometimes referred to asPEO) include product names, Polyox WSR-308 [average molecular weight:8,000,000, viscosity: 10,000-15,000 mPa·s (1% aqueous solution at 25°C.)], Polyox WSR-303 [average molecular weight: 7,000,000, viscosity:7,500-10,000 mPa·s (1% aqueous solution at 25° C.)], Polyox WSRCoagulant [average molecular weight: 5,000,000, viscosity: 5,500-7,500mPa·s (1% aqueous solution at 25° C.)], Polyox WSR-301 [averagemolecular weight: 4,000,000, viscosity: 1,650-5,500 mPa·s (1% aqueoussolution at 25° C.)], Polyox WSR-N-60K [average molecular weight:2,000,000, viscosity: 2,000-4,000 mPa·s (2% aqueous solution at 25°C.)], Polyox WSR-N-12K [average molecular weight: 1,000,000, viscosity:400-800 mPa·s (2% aqueous solution at 25° C.)], Polyox WSR-1105 [averagemolecular weight: 900,000, viscosity: 8,800-17,600 mPa·s (5% aqueoussolution at 25° C.)], Polyox WSR-205 [average molecular weight: 600,000,viscosity: 4,500-8,800 mPa·s (5% aqueous solution at 25° C.)], PolyoxWSR-N-750 [average molecular weight: 300,000, viscosity: 600-1200 mPa·s(5% aqueous solution at 25° C.)], Polyox WSR-N-80 [average molecularweight: 200,000, viscosity: 55-90 mPa·s (5% aqueous solution at 25°C.)], and Polyox WSR-N-10 [average molecular weight: 100,000, viscosity:12-50 mPa·s (5% aqueous solution at 25° C.)] (DOW).

Examples of hydoxypropyl methylcellulose (hereinafter sometimes referredto as HPMC) include product name Metolose 90SH50000 [viscosity in a 2%aqueous solution at 20° C.: 2,900-3,900 mPa·s], Metolose SB-4 (productname, Shin-Etsu Chemical Co., Ltd.) (viscosity in a 2% aqueous solutionat 20° C.: approximately 4 mPa·S), TC-5RW (product name, Shin-EtsuChemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20° C.:approximately 6 mPa·S), TC-5S (product name, Shin-Etsu Chemical Co.,Ltd.) (viscosity in a 2% aqueous solution at 20° C.: approximately 15mPa·S), TC-5R (product name, Shin-Etsu Chemical Co., Ltd.) (viscosity ina 2% aqueous solution at 20° C.: approximately 6 mPa·S), TC-5M (productname, Shin-Etsu Chemical Co., Ltd.) (viscosity in a 2% aqueous solutionat 20° C.: approximately 4.5 mPa·S), TC-5E (product name, Shin-EtsuChemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20° C.:approximately 3 mPa·S), Metolose 60SH-50 (product name, Shin-EtsuChemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20° C.:approximately 50 mPa·s), Metolose 65SH-50 (product name, Shin-EtsuChemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20° C.:approximately 50 mPa·s), Metolose 90SH-100 (product name, Shin-EtsuChemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20° C.:approximately 100 mPa·s), Metolose 90SH-100SR (product name, Shin-EtsuChemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20° C.:approximately 100 mPa·s), Metolose 65SH-400 (product name, Shin-EtsuChemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20° C.:approximately 400 mPa·s), Metolose 90SH-400 (product name, Shin-EtsuChemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20° C.:approximately 400 mPa·s), Metolose 65SH-1500 (product name, Shin-EtsuChemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20° C.:approximately 1,500 mPa·s), Metolose 60SH-4000 (product name, Shin-EtsuChemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20° C.:approximately 4,000 mPa·s), Metolose 65SH-4000 (product name, Shin-EtsuChemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20° C.:approximately 4,000 mPa·s), Metolose 90SH-4000 (product name, Shin-EtsuChemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20° C.:approximately 4,000 mPa·s), Metolose 90SH-4000SR (product name,Shin-Etsu Chemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20°C.: approximately 4,000 mPa·s), Metolose 90SH-15000 (product name,Shin-Etsu Chemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20°C.: approximately 15,000 mPa·s), Metolose 90SH-15000SR (product name,Shin-Etsu Chemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20°C.: approximately 15,000 mPa·s), and Metolose 90SH-30000 (product name,Shin-Etsu Chemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20°C.: approximately 30,000 mPa·s).

Examples of hydroxypropyl cellulose (hereinafter sometimes referred toas HPC) include HPC-SSL (product name, Nippon Soda Co., Ltd.) (viscosityin a 2% aqueous solution at 20° C.: 2.0-2.9 mPa·S), HPC-SL (productname, Nippon Soda Co., Ltd.) (viscosity in a 2% aqueous solution at 20°C.: 3.0-5.9 mPa·S), HPC-L (product name, Nippon Soda Co., Ltd.)(viscosity in a 2% aqueous solution at 20° C.: 6.0-10.0 mPa·S), HPC-M(product name, Nippon Soda Co., Ltd.) (viscosity in a 2% aqueoussolution at 20° C.: 150-400 mPa·S), and HPC-H (product name, Nippon SodaCo., Ltd.) (viscosity in a 2% aqueous solution at 20° C.: 1,000-4,000mPa·S).

Examples of methylcellulose (hereinafter sometimes referred to as MC)include Metolose SM15 (product name, Shin-Etsu Chemical Co., Ltd.)(viscosity in a 2% aqueous solution at 20° C.: approximately 15 mPa·S),Metolose SM25 (product name, Shin-Etsu Chemical Co., Ltd.) (viscosity ina 2% aqueous solution at 20° C.: approximately 25 mPa·S), Metolose SM100(product name, Shin-Etsu Chemical Co., Ltd.) (viscosity in a 2% aqueoussolution at 20° C.: approximately 100 mPa·S), Metolose SM400 (productname, Shin-Etsu Chemical Co., Ltd.) (viscosity in a 2% aqueous solutionat 20° C.: approximately 400 mPa·S), Metolose SM1500 (product name,Shin-Etsu Chemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20°C.: approximately 1,500 mPa·S), and Metolose SM4000 (product name,Shin-Etsu Chemical Co., Ltd.) (viscosity in a 2% aqueous solution at 20°C.: approximately 4,000 mPa·S).

Examples of carboxymethyl cellulose sodium (hereinafter sometimesreferred to as CMCNa) include product names, Sunrose F-30MC [viscosity:250-350 mPa·s (1% aqueous solution at 25° C.)], Sunrose F-150MC [averagemolecular weight: 200,000, viscosity: 1,200-1,800 mPa·s (1% aqueoussolution at 25° C.)], Sunrose F-600MC [viscosity: 6,000-8,000 mPa·s (1%aqueous solution at 25° C.)], Sunrose F-1000MC [average molecularweight: 420,000, viscosity: 8,000-12,000 mPa·s (the same)], SunroseF-1400MC [viscosity: 12,000-15,000 mPa·s (1% aqueous solution at 25°C.)], and Sunrose F-300MC [average molecular weight: 300,000, viscosity:2,500-3,000 mPa·s (the same)] (Nippon Paper Chemicals Co., Ltd.).

Examples of hydroxyethyl cellulose (hereinafter sometimes referred to asHEC) include product names, HEC DAICEL SE850 [average molecular weight:1,480,000, viscosity: 2,400-3,000 mPa·s (1% aqueous solution at 25°C.)], and HEC DAICEL SE900 [average molecular weight: 1,560,000,viscosity: 4,000-5,000 mPa·s (1% aqueous solution at 25° C.)](Daicelchemical Industries, Ltd.).

Examples of carboxyvinyl polymers include Carbopol 71G (viscosity:4,000-11,000 mPa·s), Carbopol 971P (viscosity: 4,000-11,000 mPa·s),Carbopol 981 (viscosity: 4,000-10,000 mPa·s), Carbopol 941 (viscosity:4,000-10,000 mPa·s), Carbopol 934 (viscosity: 30,500-39,400 mPa·s), andCarbopol 934P (viscosity: 29,400-39,400 mPa·s)(B.F.Goodrich Chemical).

These hydrogel-forming polymers may be used alone, or as an appropriatecombination of two or more thereof. A combination of different lots maybe used.

The content of the hydrogel-forming polymer is not particularly limited,so long as it is an amount to the extent that the blood concentrationprofile of the drug is not affected by the presence or absence of foodintake. The content of the hydrogel-forming polymer is, for example, 1%by weight to 70% by weight with respect to the total weight of theformulation, and 3% by weight to 70% by weight in another embodiment.The content of the hydrogel-forming polymer is 5% by weight to 70% byweight with respect to the total weight of the formulation, 10% byweight to 60% by weight in another embodiment, and 10% by weight to 40%by weight in still another embodiment. The content of thehydrogel-forming polymer is 0.1% by weight to 1,000% by weight withrespect to the weight of the drug, 1% by weight to 500% by weight inanother embodiment, and 5% by weight to 300% by weight in still anotherembodiment.

A polymer of which the viscosity (before mixing) is beyond the specificrange can be used as an appropriate combination with one or more otherpolymers, in case that the mixture obtained by mixing these pluralpolymers has a viscosity (as measured before the use) within thespecific range.

In the additive which ensures penetration of water into thepharmaceutical composition of the present invention (hydrophilic base),the amount of water necessary to dissolve 1 g of the hydrophilic base at20±5° C. is 10 mL or less, 6 mL or less in another embodiment, 5 mL orless in still another embodiment, and 4 mL or less in still anotherembodiment. When the hydrophilic base has a high solubility to water,the effect that allows water to penetrate into the formulation is high.

Examples of the hydrophilic base include water-soluble polymers, such aspolyethylene glycol [PEG: for example, product names PEG 400, PEG 1500,PEG 4000, PEG 6000, and PEG 20000 (NOF Corporation)], polyvinylpyrrolidone (PVP: for example, product name PVP K30 (BASF), and thelike; sugar alcohols, such as D-mannitol, D-sorbitol, xylitol, and thelike; saccharides, such as lactose, sucrose, anhydrous maltose,D-fructose, dextran (for example, Dextran 40), glucose, and the like;surfactants, such as polyoxyethylene hydrogenated castor oil [HCO: forexample, Cremophor RH40 (BASF), HCO-40, HCO-60 (Nikko Chemicals)],polyoxyethylene polyoxypropylene glycol [for example, Pluronic F68(Asahi Denka and the like)], polyoxyethylene sorbitan higher fatty acidesters [Tween: for example, Tween 80 (Kanto Chemical)], and the like;salts, such as sodium chloride, magnesium chloride, and the like;organic acids, such as citric acid, tartaric acid, and the like; aminoacids, such as glycine, β-alanine, lysine hydrochloride, and the like;and aminosaccharides, such as meglumine and the like.

As another embodiment, PEG, PVP, D-mannitol, D-sorbitol, xylitol,lactose, sucrose, anhydrous maltose, D-fructose, dextran, glucose,polyoxyethylene polyoxypropylene glycol, sodium chloride, magnesiumchloride, citric acid, tartaric acid, glycine, β-alanine, lysinehydrochloride, or meglumine may be used. As still another embodiment,PEG, PVP, D-mannitol, lactose, sucrose, sodium chloride, polyoxyethylenepolyoxypropylene glycol, or the like may be used.

These hydrophilic bases may be used alone, or as an appropriatecombination of two or more thereof.

The content of the hydrophilic base is not particularly limited, so longas it is an amount capable of controlling the release of the drug to theextent that the release of the drug is not affected by food. The contentof the hydrophilic base is, for example, 5% by weight to 75% by weight,5% by weight to 70% by weight in another embodiment, and 20% by weightto 60% by weight in still another embodiment.

The pharmaceutical composition for modified release of the presentinvention may be prepared as various dosage forms, which include, forexample, formulations for oral administration such as tablets, capsules(including microcapsules), granules, and powder, and formulations forparenteral administration such as suppositories (for example, rectalsuppositories or vaginal suppositories). These formulations may besafely administered orally or parenterally. Formulations for oraladministration such as tablets, capsules, and granules may be selectedin another embodiment.

The pharmaceutical composition for modified release of the presentinvention may be prepared by mixing the drug, the hydrogel-formingpolymers, and the hydrophilic base, and forming the mixture into apredetermined shape. The mixing and forming may be carried out inaccordance with conventional methods widely used in the technical fieldfor formulation. A pharmaceutically acceptable carrier may be used inthe mixing and/or forming, if desired.

In the preparation of the pharmaceutical composition for modifiedrelease of the present invention, further various pharmaceuticaladditives may be used, if desired. Such pharmaceutical additives are notparticularly limited, so long as they are pharmaceutically acceptable.Examples of the pharmaceutical additives include various organic orinorganic carrier substances which are widely used as formulationmaterials, such as fillers, lubricants, binders, and disintegratingagents. Other formulation additives such as preservatives, antioxidants,stabilizers, film coating agents, coloring agents, and sweeteners may beused, if desired.

Examples of the fillers include lactose, sucrose, D-mannitol,D-sorbitol, starch, gelatinized starch, dextrin, crystalline cellulose,low substituted hydroxypropyl cellulose, carboxymethyl cellulose sodium,gum arabic, dextrin, pullulan, light anhydrous silicic acid, syntheticaluminum silicate, magnesium aluminate metasilicate, and the like.

Examples of the lubricants include magnesium stearate, calcium stearate,talc, colloidal silica, and the like.

Examples of the binders include gelatinized starch, sucrose, gelatin,gum arabic, methylcellulose, carboxymethyl cellulose, carboxymethylcellulose sodium, crystalline cellulose, sucrose, D-mannitol, trehalose,dextrin, pullulan, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and the like.

Examples of the disintegrating agents include lactose, sucrose, starch,carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellosesodium, carboxymethyl starch sodium, light anhydrous silicic acid, lowsubstituted hydroxypropylcellulose, and the like.

Examples of the preservatives include p-hydroxybenzoate esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid, and the like.

The antioxidants are not particularly limited, so long as it can avoidthe effects of dissolution behavior. Examples of the antioxidantsinclude butylated hydroxytoluene (BHT), propyl gallate (PG),butylhydroxyanisol (BHA), ascorbic acid, sodium ascorbate, erythorbicacid, sodium nitrite, sodium bisulfite, sodium pyrosulfite, citric acid,and edetate sodium; BHT, PG, and sodium ascorbate in another embodiment;and BHT in still another embodiment.

Examples of the stabilizers include yellow ferric oxide, red ferricoxide, black iron oxide, and the like.

Examples of the film coating agents include pharmaceuticallycommonly-used bases, such as water-soluble polymers, plasticizers, andinorganic substances, or a combination thereof.

Examples of the coloring agents include water-soluble edible tarpigments (examples: edible pigments such as food red No. 2, food red No.3, food yellow No. 4, food yellow No. 5, food blue No. 1, and food blueNo. 2), water-insoluble lake pigments (examples: aluminum salts of theabove water-soluble edible tar pigments), natural pigments (examples:β-carotene, chlorophyll, and colcothar), and the like.

Examples of the sweeteners include saccharin sodium, dipotassiumglycyrrhizinate, aspartame, stevia, and the like.

These carriers or formulation additives may be used alone, or as anappropriate combination of two or more thereof.

With respect to the contents thereof, they may be used in appropriateamounts. For example, the content of the antioxidant is 0.025% by weightto 0.25% by weight with respect to the total weight of the formulation,and that of the stabilizer is 0.05% by weight to 1% by weight withrespect to the total weight of the formulation.

Hereinafter, the process of manufacturing the pharmaceutical compositionfor modified release of the present invention will be explained, thepresent invention is not limited to the following particularembodiments.

The pharmaceutical composition for modified release of the presentinvention may be prepared by known methods per se, such as drygranulation, wet granulation, fluidized bed granulation, intermittentgranulation, agitation granulation, or the like.

As a method of de-lumping or pulverizing the drug, conventional crushingor pulverizing methods may be applied, for example, using an impact mill(Hosokawa Micron Corporation; Fine Impact Mill), a dry & wet mill(Powrex Corporation: Comil), or a cutting mill granulator (DaltonCorporation; Power Mill).

As a method of pulverizing the hydrophilic base, the hydrogel-formingpolymer, or the formulation additives, conventional pulverizing methodsmay be applied, for example, using an impact mill (Hosokawa MicronCorporation; Fine Impact Mill or Sample Mill) or a jet mill (HorkosCorp; Jet Mill).

As a method of granulating the drug, conventional granulation methodsmay be used. Examples of such methods include a fluidized bedgranulation method, an intermittent granulation method, an agitationgranulation method, a high-speed agitation granulation method, atumbling fluidized bed granulation method, an extrusion granulationmethod, a pulverization granulation method, a dry granulation method,and the like. In another embodiment, examples thereof include afluidized bed granulation method, an intermittent granulation method, anagitation granulation method, a high-speed agitation granulation method,a tumbling fluidized bed granulation method, and a dry granulationmethod, and any method capable of granulating the drug may be used.Examples of a granulator include a fluidized bed granulator (forexample, Flow Coater; Freund Corporation, or GPCG; Glatt GmbH), agranulation and coating apparatus equipped with a horizontal rotatingdisc having a flat powder contact portion [for example, a centrifugalfluidizing granulator (for example, CF granulator; Freund Corporation)],a granulation and coating apparatus having a rotating disk with a flatsurface placed at the bottom of a fluidized bed and having an aerationportion (for example, Spiralflow, or Flowcoater with a rotor container;Freund Corporation), and a dry granulator in which material powder isdirectly compressed, molded, crushed, and sieved (for example, RollerCompactor; Freund Corporation).

In the dry granulation, for example, the drug, the hydrogel-formingpolymer, the hydrophilic base, and additives such as a filler may becompression-molded using a dry granulator, and then, may be crushed andsieved to obtain granulated products having a desired size.

In the wet granulation, for example, while the drug, thehydrogel-forming polymer, the hydrophilic base, and additives such as afiller is fluidized, an appropriate amount of water or a liquidcontaining the hydrophilic base and the binder may be sprayed. Theliquid containing the hydrophilic base may be prepared by dissolving ordispersing the essential component in a solvent such as water, ethanol,methanol, or the like. These solvents may be used as an appropriatemixture thereof.

The amount of water used in the granulation is not particularly limited,so long as the binder or formulation additives may be uniformlydissolved and/or suspended (dispersed) in the water. When thehydrophilic base is used in the solid form, the amount of water is notparticularly limited, so long as the hydrogel-forming polymer can begranulated.

When the hydrophilic base is used in the liquid form, the amount ofwater to the hydrogel-forming polymer is generally 10% by weight orless, 8% by weight or less in another embodiment, and 5% by weight orless in still another embodiment. A method of adding water in thegranulation is not particularly limited, so long as a nonuniform mixtureconsisting of untreated powder and aggregates, which are generallypowdery, is not generated. Examples thereof include a continuous spraymethod in which water is continuously added, an intermittent spraymethod in which a dry step (and a shaking step, if desired) is carriedout during the granulation step, and the like.

The addition rate of water in the granulation is not particularlylimited, so long as a nonuniform mixture consisting of untreated powderand aggregates, which are generally powdery, is not generated. In thefluidized bed granulation, the addition rate of water to thehydrogel-forming polymer is generally 0.1% by weight/min. to 1% byweight/min., 0.2% by weight/min. to 0.8% by weight/min. in anotherembodiment, and 0.4% by weight/min. to 0.6% by weight/min. in stillanother embodiment.

The temperature of the powder in the granulation is not particularlylimited, so long as it does not induce thermal denaturation of thehydrogel-forming polymer. The temperature is, for example, 20° C. to themelting point (62° C. to 67° C.) of the hydrogel-forming polymer, 20° C.to 50° C. in another embodiment, 20° C. to 35° C. in still anotherembodiment, and 25° C. to 30° C. in still another embodiment.

The concentration of the binder liquid as a solid content which may beused in the granulation is, for example, 1% to 20% as a formulationamount. The binder is not particularly limited, so long as it ispharmaceutically acceptable.

The binder may be added in the solid form to a granulator, and then,water may be sprayed as the binder liquid. Alternatively, the binder maybe dissolved in water, and then, the resulting binder liquid may besprayed.

An appropriate spray rate of the binder liquid varies according to aproduction method to be applied or its production scale. In a 1-kg scaleproduction by the fluidized bed granulation, the spray rate is 2 g/min.to 20 g/min., and 5 g/min. to 15 g/min. in another embodiment.

An appropriate temperature of the product in the granulation is 15° C.to 50° C., and 15° C. to 40° C. in another embodiment.

The resulting granulated products may be, for example, dried or heated.

In the drying step, an apparatus and a method are not particularlylimited, so long as the granulated products can be dried. Examples of anapparatus for drying include a fluidized bed granulator (for example,Flow Coater; Freund Corporation, or GPCG; Glatt GmbH), a granulation andcoating apparatus equipped with a horizontal rotating disc having a flatpowder contact portion [for example, a centrifugal fluidizing granulator(for example, CF granulator; Freund Corporation)], a granulation andcoating apparatus having a rotating disk with a flat surface placed atthe bottom of a fluidized bed and having an aeration portion (forexample, Spiralflow, or Flowcoater with a rotor container; FreundCorporation), and the like. The conditions for drying are notparticularly limited, so long as the granulated products may begenerally dried in the fluidized bed. The drying of the granulatedproducts will be almost completed, for example, under the conditions inwhich the dry inlet air temperature is 50° C. and the drying is carriedout until the temperature of the granulated products becomes 40° C. and,in another embodiment, under the conditions in which the dry inlet airtemperature is 40° C. and the drying is carried out until thetemperature of the granulated products becomes 30° C. As the dryingmethod, forced-air drying or drying under reduced pressure may be used.

After the completion of the granulation, an anti-oxidant may be added.

The granulated products may be sieved.

In the sieving step, an apparatus and a method are not particularlylimited, so long as the granulated products can be sieved. Examples ofan apparatus for sieving include a screen, a dry & wet mill (PowrexCorporation: Comil), a cutting mill granulator (Dalton Corporation;Power Mill), and the like. The conditions for sieving are notparticularly limited, so long as the granulated products may begenerally sieved to obtain particles having a desired size.

After the completion of the sieving, an anti-oxidant may be added.

Examples of tabletting include a direct tabletting method in which thedrug, the hydrophilic base, and the hydrogel-forming polymer are mixedwith an appropriate additive(s), and the mixture is compression-moldedto obtain tablets; a method in which a composition obtained by a wetgranulation (the granulation is carried out by spraying a mixture of thedrug, the hydrophilic base, the hydrogel-forming polymer, and additiveswith a binder liquid) or a melting granulation (the granulation iscarried out by heating a mixture of the drug, the hydrophilic base, thehydrogel-forming polymer, and an appropriate low-melting substance) isformed into tablets; and the like.

A rotary tabletting machine, a single punch tabletting machine, and thelike may be used as a tabletting machine. A method as well as anapparatus is not particularly limited, so long as a compression-moldedproduct (preferably tablets) can be pharmaceutically produced.

After the tabletting, the obtained tablets may be dried. The initialwater content of the tablet is, for example, 2% by weight/tablet orless, 1.5% by weight/tablet or less in another embodiment, and 0.9% byweight/tablet or less in still another embodiment.

After the tabletting, the obtained tablets may be film coated using apan coating machine at an amount of 1% by weight to 5% by weight pertablet.

EXAMPLES

The present invention will now be further illustrated by, but is by nomeans limited to, the following Examples.

Example 1

In a mortar, 10 g of compound A, 2.5 g of polyethylene oxide (Dowchemical; product name: WSR N-60K; The same compound was used in thefollowing Examples, unless otherwise specified.), and 7.5 g ofpolyethylene glycol (Sanyo Chemical Industries, Ltd.; PEG 6000; The samecompound was used in the following Examples.) were mixed well. Themixture was formed into tablets using Autograph (Shimadzu; The sameapparatus was used in the following Examples.) to obtain apharmaceutical composition for modified release of the present inventionhaving a tablet weight of 400 mg.

Example 2

In a mortar, 10 g of compound A, 3.5 g of polyethylene oxide, and 6.5 gof polyethylene glycol were mixed well, and the mixture was formed intotablets using Autograph to obtain a pharmaceutical composition formodified release of the present invention having a tablet weight of 400mg.

Example 3

In a mortar, 10 g of compound A, 6.25 g of polyethylene oxide, and 5 gof polyethylene glycol were mixed well, and the mixture was formed intotablets using Autograph to obtain a pharmaceutical composition formodified release of the present invention having a tablet weight of 425mg.

Example 4

In a mortar, 10 g of compound A, 5 g of hydroxypropyl methylcellulose(Shin-Etsu Chemical Co., Ltd.; HPMC90SH-4000SR), and 5 g of polyethyleneglycol were mixed well, and the mixture was formed into tablets usingAutograph to obtain a pharmaceutical composition for modified release ofthe present invention having a tablet weight of 400 mg.

Example 5

In a mortar, 10 g of compound A, 5 g of hydroxypropyl methylcellulose(Shin-Etsu Chemical Co., Ltd.; HPMC90SH-100000SR), and 5 g ofpolyethylene glycol were mixed well, and the mixture was formed intotablets using Autograph to obtain a pharmaceutical composition formodified release of the present invention having a tablet weight of 400mg.

Example 6

In a mortar, 10 g of compound A, 7.5 g of hydroxypropyl methylcellulose(Shin-Etsu Chemical Co., Ltd.; HPMC90SH-100SR), and 2.5 g ofpolyethylene glycol were mixed well, and the mixture was formed intotablets using Autograph to obtain a pharmaceutical composition formodified release of the present invention having a tablet weight of 400mg.

Example 7

After 400 g of compound A, 140 g of polyethylene oxide, 251.2 g ofpolyethylene glycol, 0.8 g of finely ground BHT (Merck; The samecompound was used in the following Examples.) and 8 g of magnesiumstearate were weighed out, these compounds were mixed using a mixer. Themixture was compression-molded using Roller Compactor Mini (FreundCorporation) and sieved to obtain a pharmaceutical composition formodified release (granules) of the present invention. The obtainedgranules were formed into tablets using a rotary tabletting machine(Hata Iron Works Co., Ltd.; The same apparatus was used in the followingExamples.) to obtain a pharmaceutical composition for modified release(tablets) of the present invention having a tablet weight of 400 mg.

Example 8

The tablets obtained in Example 7 were coated with a film coating agent[Colorcon; Opadry (containing yellow ferric oxide as a stabilizer); Thesame agent was used in the following Examples, unless otherwisespecified.] dispersed into water to obtain a pharmaceutical compositionfor modified release (tablets) of the present invention.

Example 9

Into a fluidized bed granulating apparatus GPCG-5 (Freund Corporation;The same apparatus was used in the following Examples.), 1500 g ofde-lumped compound A, 1050 g of polyethylene oxide, and 1764 g ofpolyethylene glycol were loaded, and granulated with 1350 g of a 10% byweight aqueous solution of hydroxypropyl cellulose (Nippon Soda Co.,Ltd.; HPC-SL; The same compound was used in the following Examples.) toobtain a pharmaceutical composition for modified release (granules) ofthe present invention. The resulting pharmaceutical composition formodified release (granules) of the present invention was sieved andmixed with 4 g of finely ground BHT and 30 g of magnesium stearate, andthe mixture was formed into tablets using a rotary tabletting machine toobtain a pharmaceutical composition for modified release (tablets) ofthe present invention having a tablet weight of 300 mg. The obtainedtablets were spray-coated with an aqueous dispersion of the film coatingagent using HiCoater to obtain a pharmaceutical composition for modifiedrelease (tablets) of the present invention having a tablet weight of 309mg.

Example 10

Into a fluidized bed granulating apparatus GPCG-5, 1500 g of de-lumpedcompound A, 1050 g of polyethylene oxide, 1764 g of polyethylene glycol,and 135 g of hydroxypropyl cellulose (HPC-SL) were loaded, andgranulated with purified water to obtain a pharmaceutical compositionfor modified release (granules) of the present invention. The resultingpharmaceutical composition for modified release (granules) of thepresent invention was sieved and mixed with 4 g of finely ground BHT and30 g of magnesium stearate, and the mixture was formed into tabletsusing a rotary tabletting machine to obtain a pharmaceutical compositionfor modified release (tablets) of the present invention having a tabletweight of 300 mg. The obtained tablets were spray-coated with an aqueousdispersion of the film coating agent using HiCoater to obtain apharmaceutical composition for modified release (tablets) of the presentinvention having a tablet weight of 309 mg.

Example 11

After 400 g of compound A, 100 g of polyethylene oxide, 290 g ofpolyethylene glycol, 2 g of finely ground BHT, and 8 g of magnesiumstearate were weighed out, these compounds were mixed using a mixer. Themixture was compression-molded using Roller Compactor Mini and sieved toobtain a pharmaceutical composition for modified release (granules) ofthe present invention. The obtained granules were formed into tabletsusing a rotary tabletting machine to obtain a pharmaceutical compositionfor modified release (tablets) of the present invention having a tabletweight of 400 mg.

Example 12

In a mortar, 10 g of compound A, 2.5 g of polyethylene oxide (Dowchemical; product name: WSR Coagulant), and 12.5 g of polyethyleneglycol were mixed well. The mixture was formed into tablets usingAutograph to obtain a pharmaceutical composition for modified release ofthe present invention having a tablet weight of 400 mg.

Example 13

In a mortar, 10 g of compound A, 0.5 g of polyethylene oxide (Dowchemical; product name: WSR 301), and 5 g of polyethylene glycol weremixed well. The mixture was formed into tablets using Autograph toobtain a pharmaceutical composition for modified release of the presentinvention having a tablet weight of 310 mg.

Example 14

In a mortar, 5 g of compound A, 15 g of polyethylene oxide, and 5 g ofpolyethylene glycol were mixed well. The mixture was formed into tabletsusing Autograph to obtain a pharmaceutical composition for modifiedrelease of the present invention having a tablet weight of 250 mg.

Example 15

In a mortar, 10 g of compound A, 10 g of polyethylene oxide (Dowchemical; product name: WSR N-12K), and 5 g of D-mannitol (Towa ChemicalIndustry Co., Ltd; product name: Mannit P) were mixed well. The mixturewas formed into tablets using Autograph to obtain a pharmaceuticalcomposition for modified release of the present invention having atablet weight of 500 mg.

Example 16

In a mortar, 2 g of compound A, 2 g of polyethylene oxide, and 10 g ofpolyethylene glycol were mixed well. The mixture was formed into tabletsusing Autograph to obtain a pharmaceutical composition for modifiedrelease of the present invention having a tablet weight of 350 mg.

Example 17

Into a fluidized bed granulating apparatus GPCG-5, 400 g of de-lumpedcompound A, 1120 g of polyethylene oxide, and 2313.6 g of polyethyleneglycol were loaded, and granulated with 1200 g of a 10% by weightaqueous solution of hydroxypropyl cellulose to obtain a pharmaceuticalcomposition for modified release (granules) of the present invention.The resulting pharmaceutical composition for modified release (granules)of the present invention was sieved and mixed with 6.4 g of finelyground BHT and 40 g of magnesium stearate, and the mixture was formedinto tablets using a rotary tabletting machine to obtain apharmaceutical composition for modified release (tablets) of the presentinvention having a tablet weight of 250 mg. The obtained tablets werespray-coated with an aqueous dispersion of the film coating agent(containing yellow ferric oxide and red ferric oxide as stabilizers)using HiCoater to obtain a pharmaceutical composition for modifiedrelease (tablets) of the present invention having a tablet weight of257.5 mg.

The formulations in Examples 1 to 17 are shown in Tables 1 to 3.

TABLE 1 Examples 1 2 3 4 5 6 compound A (g) 10 10 10 10 10 10 PEO WSRN-60K (g) 2.5 3.5 6.25 — — — HPMC 90SH-4000SR (g) — — — 5 — — HPMC90SH-100000SR (g) — — — — 5 — HPMC 90SH-100SR (g) — — — — — 7.5 PEG (g)7.5 6.5 5 5 5 2.5

TABLE 2 Examples 7 8 9 10 11 compound A (g) 400 400 1500 1500 400 PEOWSR N-60K (g) 140 140 1050 1050 100 PEG (g) 251.2 251.2 1764 1764 290HPC-SL (g) — — 135 135 — magnesium stearate (g) 8 8 30 30 8 BHT (g) 0.80.8 4 4 2 film coating agent (g) — 23.7 134 134 —

TABLE 3 Examples 12 13 14 15 16 17 compound A (g) 10 10 5 10 2 400 PEOWSR N-60K (g) — — 15 — 2 1120 PEO WSR coagulant (g) 2.5 — — — — — PEOWSR 301 (g) — 0.5 — — — — PEO WSR N-12K (g) — — — 10 — — PEG (g) 12.5 55 — 10 2313.6 D-mannitol — — — 5 — — HPC-SL (g) — — — — — 120 magnesiumstearate — — — — — 40 (g) BHT (g) — — — — — 6.4 film coating agent — — —— — 120 (g)

Comparative Example 1

After 400 g of pulverized compound A was mixed with 1200 g ofD-mannitol, 320 g of purified water was further added, and the whole waskneaded using an agitation granulator (Powrex Corporation; VG-25). Theresulting aggregate was sieved through a screen having an opening of 850μm, and dried using a fluidized bed granulating apparatus (FreundCorporation; FLO-1). The dried products were sieved through a screenhaving an opening of 500 μm, and filled into No. 1 capsules at a contentof 320 mg per capsule to obtain a pharmaceutical composition forcomparison containing 80 mg of compound A.

EXPERIMENTAL EXAMPLES

1. Dissolution test

The pharmaceutical compositions prepared in Examples 2, 8, and 9 weresubjected to a dissolution test carried out in accordance with a USPdissolution test (paddle method). As a test fluid, 900 mL of a phosphatebuffer (pH 6.8) was used. The pharmaceutical composition prepared inComparative Example 1 was tested in accordance with a dissolution test,method 2 described in the Japanese Pharmacopoeia. As a test fluid, 900mL of a Mc. Ilvain buffer (pH 6.8) was used, and the paddle rotationspeed was 50 rpm.

The results are shown in Table 4. The dissolution rate after 1.5 hoursof the pharmaceutical composition for modified release prepared in eachExample was less than 40%. By contrast, the composition prepared inComparative Example showed a high dissolution rate of 85% or more after0.5 hour.

TABLE 4 Comparative Example 2 Example 8 Example 9 Example 1 0.5 hr. — —— 95% 1.5 hr. 35% 39% 32% — 2.5 hr. 57% 61% 54% — 4.5 hr. 93% 95% 92% —

2. Stability Test

Plastic bottles were filled with the pharmaceutical composition formodified release prepared in Example 11, and sealed. These bottles werepreserved under the conditions at 40° C. and 75% RH or at 60° C. for 3months. After the preservation, each pharmaceutical composition wassubjected to a dissolution test carried out in accordance with a USPdissolution test (paddle method). As a test fluid, 900 mL of a phosphatebuffer (pH 6.8) was used. The results are shown in FIG. 1. Theacceleration of a dissolution rate was not observed after thepreservation for 3 months under the conditions at 40° C. and 75% RH orat 60° C., and the results were indicative that the pharmaceuticalcomposition was stable.

The pharmaceutical compositions for modified release prepared inExamples 8 and 9 were packed with alminum/alminum blister, and preservedunder the conditions at 40° C. and 75% RH for 6 months. After thepreservation, each pharmaceutical composition was subjected to adissolution test carried out in accordance with a USP dissolution test(paddle method). As a test fluid, 900 mL of a phosphate buffer (pH 6.8)was used. As a result, changes in the dissolution rate at the pointshowing a dissolution rate of approximately 50% were 2% and 3%, withrespect to the pharmaceutical compositions prepared in Examples 8 and 9,respectively, and the results were indicative that the pharmaceuticalcompositions were stable.

The pharmaceutical composition for modified release prepared in Example17 was exposed to 1.2 million Lux·hr of light. After the exposure, thepharmaceutical composition was subjected to a dissolution test carriedout in accordance with a USP dissolution test (paddle method). As a testfluid, 900 mL of a phosphate buffer (pH 6.8) was used. As a result, thechange in the dissolution rate at the point showing a dissolution rateof approximately 50% was less than 1%, and the result was indicativethat the pharmaceutical composition was stable.

3. Pharmacokinetics (PK) Test in Human

The pharmaceutical composition for modified release prepared in Example8, which contained the equivalent corresponding to 200 mg of compound A,was administered to healthy persons in a fasted state or after 30minutes from the intake of food, and the plasma levels of the drug weremeasured.

For comparison, 2 capsules of the pharmaceutical composition(conventional formulation) prepared in Comparative Example 1, whichcontained the equivalent corresponding to 160 mg of compound A, wasadministered to healthy persons in a fasted state or after 30 minutesfrom the intake of food, and the plasma levels of the drug weremeasured.

With respect to the conventional formulation, the rate of decrease ofCmax in the fed state was 67%, in comparison with that in a fastedstate, and the rate of decrease of AUC was 47% (Cmax in the fasted statewas approximately three times higher than that in the fed state). Withrespect to the pharmaceutical composition for modified release of thepresent invention, the rate of decrease of Cmax in free-feeding was 42%,in comparison with that in a fasted state, and the rate of decrease ofAUC was 25%. These results indicated that the reductions of Cmax and AUCcaused by food intake could be significantly alleviated by thepharmaceutical composition for modified release of the presentinvention.

INDUSTRIAL APPLICABILITY

According to the present invention, a pharmaceutical composition formodified release in which the changes in AUC and Cmax caused by foodintake can be decreased by controlling a releasing rate of the activeingredient can be provided.

As above, the present invention was explained with reference toparticular embodiments, but modifications and improvements obvious tothose skilled in the art are included in the scope of the presentinvention.

1. A pharmaceutical composition for modified release, comprising (1) 10mg to 200 mg of(R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]aceticacid anilide, or a pharmaceutically acceptable salt thereof, (2) atleast one additive which ensures penetration of water into thepharmaceutical composition and which has a solubility such that thevolume of water required for dissolving 1 g of the additive is 10 mL orless, and (3) a hydrogel-forming polymer having an average molecularweight of approximately 100,000 to 5,000,000, or a viscosity of 12 mPa·sat a 5% aqueous solution at 25° C. to 7500 mPa·s at a 1% aqueoussolution at 25° C., wherein the hydrogel-forming polymer is present inan amount of 1% by weight to 40% by weight with respect to the totalweight of the pharmaceutical composition; and wherein a drug dissolutionrate from the pharmaceutical composition is 75% or less after 1.5 hours,and 75% to 100% after 7 hours from the beginning of a dissolution test.2. The pharmaceutical composition for modified release according toclaim 1, wherein the additive which ensures penetration of water intothe pharmaceutical composition is one compound, or two or more compoundsselected from the group consisting of polyethylene glycol,polyvinylpyrrolidone, D-mannitol, D-sorbitol, xylitol, lactose, sucrose,anhydrous maltose, D-fructose, dextran, glucose, polyoxyethylenehydrogenated castor oil, polyoxyethylene polyoxypropylene glycol,polyoxyethylene sorbitan higher fatty acid ester, sodium chloride,magnesium chloride, citric acid, tartaric acid, glycine, β-alanine,lysine hydrochloride, and meglumine.
 3. The pharmaceutical compositionfor modified release according to claim 2, wherein the additive whichensures penetration of water into the pharmaceutical composition is onecompound, or two or more compounds selected from the group consisting ofpolyethylene glycol, polyvinylpyrrolidone, D-mannitol, lactose, sucrose,sodium chloride, and polyoxyethylene polyoxypropylene glycol.
 4. Thepharmaceutical composition for modified release according to claim 1,wherein an amount of the additive which ensures penetration of waterinto the pharmaceutical composition is 5% by weight to 75% by weightwith respect to the total weight of the pharmaceutical composition. 5.The pharmaceutical composition for modified release according to claim4, wherein an amount of the additive which ensures penetration of waterinto the pharmaceutical composition is 5% by weight to 70% by weightwith respect to the total weight of the pharmaceutical composition. 6.The pharmaceutical composition for modified release according to claim1, wherein the hydrogel-forming polymer is one compound, or two or morecompounds selected from the group consisting of polyethylene oxide,hydoxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose sodium, hydroxyethyl cellulose, and a carboxyvinyl polymer. 7.The pharmaceutical composition for modified release according to claim6, wherein the hydrogel-forming polymer is one compound, or two or morecompounds selected from the group consisting of polyethylene oxide,hydoxypropyl methylcellulose, and hydroxypropyl cellulose.
 8. Thepharmaceutical composition for modified release according to claim 1,further comprising an antioxidant.
 9. The pharmaceutical composition formodified release according to claim 8, wherein the antioxidant is onecompound, or two or more compounds selected from the group consisting ofbutyl hydroxytoluene, propyl gallate, and sodium ascorbate.
 10. Thepharmaceutical composition for modified release according to claim 9,wherein the antioxidant is butyl hydroxytoluene.
 11. The pharmaceuticalcomposition for modified release according to claim 8, wherein an amountof the antioxidant is 0.025% by weight to 0.25% by weight.
 12. Thepharmaceutical composition for modified release according to claim 1,further comprising a stabilizer.
 13. The pharmaceutical composition formodified release according to claim 12, wherein the stabilizer is onecompound, or two or more compounds selected from the group consisting ofyellow ferric oxide, red ferric oxide, and black iron oxide.
 14. Thepharmaceutical composition for modified release according to claim 13,wherein the stabilizer is yellow ferric oxide and/or red ferric oxide.15. The pharmaceutical composition for modified release according toclaim 12, wherein an amount of the stabilizer is 0.05% by weight to 1%by weight.
 16. A process of manufacturing a pharmaceutical compositionfor modified release, characterized by comprising mixing (1)(R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]aceticacid anilide, or a pharmaceutically acceptable salt thereof with (2) atleast one additive which ensures penetration of water into thepharmaceutical composition and which has a solubility such that thevolume of water required for dissolving 1 g of the additive is 10 mL orless and (3) a hydrogel-forming polymer having an average molecularweight of approximately 100,000 or more, or a viscosity of 12 mPa·s ormore at a 5% aqueous solution at 25° C., wherein an amount of theadditive is 5% by weight to 75% by weight with respect to the totalweight of the pharmaceutical composition, and an amount of thehydrogel-forming polymer is 1% by weight to 40% by weight with respectto the total weight of the pharmaceutical composition.
 17. The processaccording to claim 16, wherein the additive which ensures penetration ofwater into the pharmaceutical composition is one compound, or two ormore compounds selected from the group consisting of polyethyleneglycol, polyvinylpyrrolidone, D-mannitol, D-sorbitol, xylitol, lactose,sucrose, anhydrous maltose, D-fructose, dextran, glucose,polyoxyethylene hydrogenated castor oil, polyoxyethylenepolyoxypropylene glycol, polyoxyethylene sorbitan higher fatty acidester, sodium chloride, magnesium chloride, citric acid, tartaric acid,glycine, β-alanine, lysine hydrochloride, and meglumine.
 18. The processaccording to claim 16, wherein the hydrogel-forming polymer is onecompound, or two or more compounds selected from the group consisting ofpolyethylene oxide, hydoxypropyl methylcellulose, hydroxypropylcellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose, and acarboxyvinyl polymer.
 19. The pharmaceutical composition for modifiedrelease according to claim 1, wherein a drug dissolution rate from thepharmaceutical composition is 92%, 93% or 95% after 4.5 hours from thebeginning of a dissolution test.
 20. The pharmaceutical composition formodified release according to claim 1, wherein the average molecularweight of the hydrogel-forming polymer is 100,000 to 2,000,000.
 21. Amethod of reducing an effect of food intake, comprising the step ofadministering a pharmaceutical composition comprising a drug, which is apharmaceutical composition for modified release, comprising (1) 10 mg to200 mg of(R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]aceticacid anilide, or a pharmaceutically acceptable salt thereof, (2) atleast one additive which ensures penetration of water into thepharmaceutical composition and which has a solubility such that thevolume of water required for dissolving 1 g of the additive is 10 mL orless, and (3) a hydrogel-forming polymer having an average molecularweight of approximately 100,000 to 5,000,000, or a viscosity of 12 mPa·sat a 5% aqueous solution at 25° C. to 7500 mPa·s at a 1% aqueoussolution at 25° C., wherein the hydrogel-forming polymer is present inan amount of 1% by weight to 40% by weight with respect to the totalweight of the pharmaceutical composition; and wherein a drug dissolutionrate from the pharmaceutical composition is 75% or less after 1.5 hours,and 75% or more to 100% or less after 7 hours from the beginning of adissolution test.
 22. The method according to claim 21, wherein theadditive which ensures penetration of water into the pharmaceuticalcomposition is one compound, or two or more compounds selected from thegroup consisting of polyethylene glycol, polyvinylpyrrolidone,D-mannitol, D-sorbitol, xylitol, lactose, sucrose, anhydrous maltose,D-fructose, dextran, glucose, polyoxyethylene hydrogenated castor oil,polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan higherfatty acid ester, sodium chloride, magnesium chloride, citric acid,tartaric acid, glycine, β-alanine, lysine hydrochloride, and meglumine.23. The method according to claim 22, wherein the additive which ensurespenetration of water into the pharmaceutical composition is onecompound, or two or more compounds selected from the group consisting ofpolyethylene glycol, polyvinylpyrrolidone, D-mannitol, lactose, sucrose,sodium chloride, and polyoxyethylene polyoxypropylene glycol.
 24. Themethod according to claim 21, wherein an amount of the additive whichensures penetration of water into the pharmaceutical composition is 5%by weight to 75% by weight with respect to the total weight of thepharmaceutical composition.
 25. The pharmaceutical composition formodified release according to claim 24, wherein an amount of theadditive which ensures penetration of water into the pharmaceuticalcomposition is 5% by weight to 70% by weight with respect to the totalweight of the pharmaceutical composition.
 26. The method according toclaim 21, wherein the hydrogel-forming polymer is one compound, or twoor more compounds selected from the group consisting of polyethyleneoxide, hydoxypropyl methylcellulose, hydroxypropyl cellulose,carboxymethyl cellulose sodium, hydroxyethyl cellulose, and acarboxyvinyl polymer.
 27. The method according to claim 26, wherein thehydrogel-forming polymer is one compound, or two or more compoundsselected from the group consisting of polyethylene oxide, hydoxypropylmethylcellulose, and hydroxypropyl cellulose.
 28. The pharmaceuticalcomposition for modified release according to claim 21, furthercomprising an antioxidant.
 29. The method according to claim 28, whereinthe antioxidant is one compound, or two or more compounds selected fromthe group consisting of butyl hydroxytoluene, propyl gallate, and sodiumascorbate.
 30. The method according to claim 29, wherein the antioxidantis butyl hydroxytoluene.
 31. The method according to claim 28, whereinan amount of the antioxidant is 0.025% by weight to 0.25% by weight. 32.The method according to claim 21, further comprising a stabilizer. 33.The method according to claim 32, wherein the stabilizer is onecompound, or two or more compounds selected from the group consisting ofyellow ferric oxide, red ferric oxide, and black iron oxide.
 34. Themethod according to claim 33, wherein the stabilizer is yellow ferricoxide and/or red ferric oxide.
 35. The method according to claim 32,wherein an amount of the stabilizer is 0.05% by weight to 1% by weight.36. The method according to claim 21, wherein a drug dissolution ratefrom the pharmaceutical composition is 92%, 93% or 95% after 4.5 hoursfrom the beginning of a dissolution test.
 37. The method according toclaim 21, wherein the average molecular weight of the hydrogel-formingpolymer is 100,000 to 2,000,000.